N-desacetyl colchiceine for the treatment of gout



United States Patent f The present invention relates to the use of N-desacetyl colchiceine in the treatment of acute gout to alleviate the symptoms thereof without causing excessive toxic reactions.

Over the course of approximately 1500 years colchicine and extracts of the plant Colchicum aurumnale have been used medically in the treatment of acute gout. The cause of the anti-gout effect of these materials is not certain and the mechanism of the dramatic relief afforded by them in acute attacks of gouty arthritis is not fully understood.

In addition to the anti-gout elfect of colchicine and the extracts containing it, it also has a striking anti-mitotic effect. In the proper concentrations colchicine can arrest plant and animal cell division both in vitro and in vivo. The toxicity of colchicine and the extracts containing it is high and various side effects, such as gastrointestinal disturbances occur in its use as an anti-gout agent. If used in greater dosages than those ordinarily used in treatment of gout, other side effects such as agranulocytosis and depilation occur. The administration of colchicine in persons afliicted with acute gout must be made with extreme care as the amount required to alleviate an attack is approximately 4 to 8 mgIn. given over a period of 8 to 24 hours and this dosage is sufiicient in a number of instances to give rise to considerable side effects, such as nausea, vomiting, diarrhea, etc. In addition, when treating patients with chronic gout care must be taken to avoid a build-up in the system as such accumulation gives rise to the above-mentioned undesired side elfects.

A number of colchicine derivatives have been studiexi and proposed for use in treatment of acute gout but it has been found that either these derivatives were comparable in all respects to colchicine itself or have even greater toxic manifestations. Among these derivatives have been suggested colchiceine, desacetyl methyl colchicine and colchicoside. Of these compounds, desacetyl methyl 'colchicine is as effective as an anti-gout agent as colchicine itself and has little or no gastrointestinal toxicity. However, this compound has been found to be considerably more anti-mitotic than colchicine and its continued use gives rise to agranulocytosis and depilation. Colchiceine has been found to have little antigout activity when given orally. Colchicoside is not as effective as an anti-gout agent as is the parent colchicine.

An object of the invention is the development of a process for the treatment of persons afllicted with acute gout by administering to said persons a therapeutic amount of N-desacetyl colchiceine.

Another object of the invention is the development of a treatment for persons afiiicted with acute gout by administering to them a therapeutic agent having a high anti-gout activity with a low toxicity and anti-mitotic activity.

These and other objects of the invention will become more apparent as the description thereof proceeds.

I have found that an analogue of colchicine, the known compound, N-desacetyl colchiceine, can be administered to persons affiicted with acute gout with exceptionally good results. Treatment with this compound has been efiective in relieving the symptoms of acute gout in a large number of patients. At the same time it has been 3,006,812 Patented Oct. 31, 1961 found that the usual toxic manifestations of the colchicine derivatives are pesent in little, if any, amounts. No significant toxicity was found even after chronic prophylactic administration. The tolerance in the gastro-intestinal tract is excellent and experimental studies have indicated that the compound has almost no anti-mitotic effect. N-desacety1 colchiceine has the following chemical structure:

onio NH: OHsO I CHsO L This compound differs from colchicine in that the acetyl group in the side chain of the second ring has been replaced by a hydrogen and the methoxy radical in the third ring has been replaced by a hydroxy radical. This compound has also been referred to as trirnethylcolchicinic acid (TMCA). This compound is produced in excellent yields by refluxing colchicine in a 1:1 mixture of methanol and concentrated hydrochloric acid. This process is described by Fernholz, Angew, Chim. 65, 319 (1953).

Although the name, N-desacetyl colchiceine, suggests that the compound has a structure similar to colchiceine, it actually has the tautomeric structure of Formula I. This terminology was applied to the compound because it was first produced by heating colchiceine in concentrated hydrochloric acid. (See Zeisel, Mh. Chem., vol. 9 [1888], page 1.) The tautomeric shift occurs during the hydrolysis of the amide portion of colchiceine.

N-desacetyl colchiceine is readily soluble in water and is administered to patients suffering from acute gout in the form of capsules or tablets similarly to colchicine tablets. For effectiveness 5 to 10 milligrams given orally are usually sutiicient, however, doses up to 16 mgm. have been given. Because of the lack of side efiects this dos-age can be given in one dose rather than the usual dosage schedule followed with colchicine where an initial dose of 1 mgm. is followed by a dose of 0.5 mgm. each hour until either a total of 5 to 8 mmn. are ingested or toxic symptoms appear. Since N-desacetyl colchiceine is readily absorbed when given orally and its effect is rapid, there is no occasion to utilize it by injecting it intravenously. However, it can also be so used if desired for example in treatment of postoperative patients or those who cannot swallow, as it is readily soluble in water or dilute alcohol solutions.

For chronic phophylactic administration it is recommended that the drug be taken in doses of 0.5 mgm. to 5.0 mgm., preferably between 1.0 mgm. to 3.0 mgm., daily or every other day, the exact amount and schedule to be modified according to the requirements of the case. To be efiective, in addition N-des'acetyl colchiceine should be taken in larger abortive doses immediately upon the first twinge of articular pain. No tolerance was apparent in the course of prophylaxis and no diminution in effect was observed upon repeated administration. Due to the much lower toxicity of N-desacetyl colchiceine, the therapeutic index, i.e., the level of toxic manifestations over the effective therapeutic dose is considerably greater than that of colchicine or the other colchicine derivatives proposed for treatment of acute gout and regular ingestion of N- desacetyl colchiceine can be carried out with no fear of complications. The treatment of acute gout with N-desacetyl colchiceine can be combined with other therapeutic types of treatment for the same or related diseases. The treatment with N-desacetyl colchiceine can be combined with all other methods for the treatment of gout such as diet, abundant fluids, and other drugs.

The best results are obtained when the treatment with N-desacetyl colchiceine is started as soon as possible after an attack of acute gout begins. The early treatment is more effective in alleviating the symptoms and a long delay decreases the effectiveness of the treatment somewhat.

The following examples are illustrative of the principles of the invention. It is to be understood that other expedients known to those skilled in the art may be employed without departing from the scope of the invention.

EXAMPLE I Production of N-desacetyl colchiceine 5 gm. of colchicine (Merck) were dissolved in 30 cc. of methanol and after addition of 30 cc. of concentrated hydrochloric acid, the mixture was refluxed for 12 hours (overnight). The dark brown solution was then admixed with about 100 cc. of water and neutralized with dilute sodium hydroxide (pH 6.5 to 7), whereby the major portion of the reaction product precipitated out. The mixture was shaken twice with 100 to 150 cc. portions of chloroform, the chloroform solution was dried over so- EXAMPLE II Therapeutic treatment with N-desacetyl colchiceine Five patients with acute gout were selected for treatment. They demonstrated acute arthritis, associated in all with hyperuricemia. In most patients, there had been preceding acute attacks of gout, and many had had typical responses to the administration of colchicine. In these patients the diagnosis of recurrent acute gout was well established. No patient was included in this test in whom the diagnosis of acute gout was uncertain.

A good response to therapy was arbitrarily defined as the 75 percent or greater clearance of all objective manifestations of acute gout within 48 hours after therapy. This arbitrary criterion for successful therapy has not been completely satisfactory; in some patients, partial responses to therapy, less than 75 percent clearing, occurred. For the purposes of this study, however, some definition of specific response to therapy was necessary. The patients showing inadequate response to N-desacetyl colchiceine were then given oral or intravenous colchicine in therapeutic doses. This was done to determine the susceptibility of these individual episodes of acute gout to any colchicine-like agent.

Four of the five patients responded to the treatment with N-desacetyl colchiceine when given the drug orally in a single dose of 5 to 6 mgm. No toxicity was seen in this group. The one patient who failed to respond also failed to respond to a subsequent therapeutic dose of colchicine.

EXAMPLE H1 34 patients with symptoms of acute gout were treated by oral administration of from 4.0 to 8.0 mgm. single doses of N-desacetyl colchiceine. 26 of these patients responded excellently and no significant toxicity was noted. Two patients developed mild transitory diarrhea but no agranulocytosis or depilation was seen, even after a follow-up of as long as one year. Of the 8 patients who did not respond fully, 4 patients had some response to the treatment and only 4 patients failed to respond.

EXAMPLE IV 7 patients with acute recurrent gout were placed on a prophylactic administration of from 1.0 mgm. to 3.0 mgm. of N-desacetyl colchiceine daily for periods of 1 to 3 months. These patients had no attacks during the period of therapy and no toxic effects were noted.

The following examples are case histories of individual patient response to the treatment of N-desacetyl colchiceine for acute gout and recurrent acute gout.

EXAMPLE V A 48-year-old obese white male presented himself to the emergency room of a hospital with a 6 hour history of acute inflammatory swelling and severe, agonizing pain overlying the right first metatarsal phalangeal joint. A diagnosis of acute gout was made and the patient was given 5 milligrams of N-desacetyl colchiceine. 4 hours later, he noted a marked diminution in pain and within 8 hours all pain was gone. The redness began to disappear in about 12 hours and in 24 hours his toe joint was essentially normal. He had no diarrhea, intestinal disturbances of other sorts, nausea or vomiting.

EXAMPLE VI A 62-year-old postmenopausal white female was admitted to the hospital because of embolization to her left leg. She had had a history of known recurrent acute gout for 6 years but had been on no prophylactic medication. On the 7th day of her hospital stay she developed a temperature elevation to 101 and an acute, severely painful swelling of the right ankle. This was diagnosed as a recurrence of her acute gout; 8 milligrams of N-desacetyl colchiceine was given at once and within 12 hours her temperature had returned to normal and her joint pains had markedly diminished. The redness and swelling disappeared within 48 hours.

EXAMPLE VII A patient was a 48-year-old postsurgical menopausal female who had had acute recurrent episodes of gout occurring approximately every 3 to 4 months. This patient was given 2. milligrams of N-desacetyl colchiceine each day for a period of 3 months. During this time she did not have any attack of gout and there were no gastrointestinal, hematological or other side effects.

The preceding examples are not to be considered as limiting the invention in any fashion. Such changes and modifications as would occur to one skilledin the art can be made in the invention without departing from the scope thereof or the spirit of the appended claims.

I claim:

1. The process of alleviating the pain and effecting treatment in cases of gout in persons without exerting excessive toxic reactions which comprises administering to said persons afflicted with acute gout a dose of up to about 16 mgrn. of N-desacetyl-colchiceine.

2. The process of treating persons afflicted with gout which comprises administering to said persons a dose of up to about 16 mgm. of N-desacetyl colchiceine.

References Cited in the file of this patent UNITED STATES PATENTS 2,823,206 Ullyot Feb. 11, 1958 

1. THE PROCESS OF ALLEVIATING THE PAIN AND EFFECTING TREATMENT IN CASES OF GOUT IN PERSONS WITHOUT EXERTING EXCESSIVE TOXIC REACTIONS WHICH COMPRISES ADMINISTERING TO SAID PERSONS AFFLICTED WITH ACUTE GOUT A DOSE OF UP TO ABOUT 16 MGM. OF N-DESACETYL-COLCHICEINE. 